Abnormal Lymphoid Development & Granuloma Formation
Summary
Granulomas, intricate entities composed of immune and structural cells, are typically orchestrated by the immune system as a defense mechanism against infections or foreign substances, albeit involuntarily inducing pathologies. Recent research posits that the symbiotic network between immune and structural cells sustains granulomas, but the underlying molecular and cellular machinations of granuloma genesis remain nebulous. In the study at hand, the researchers dissect the molecular and cellular architecture of granulomas through the synergistic use of single-cell transcriptome sequencing and spatial transcriptomics, founded on paired specimens from a dozen patients with enduring cutaneous nodular disease. The study unveiled transcriptional processes akin to lymphoid organ development in granulomas and unearthed shared pathological mechanisms across individuals and organs, thus furnishing prospective bullseyes for therapeutic countermeasures against granulomas.
Fig.1 Graphical abstract. (Krausgruber, 2023)
Research Criteria
The conceptual crux of this manuscript lies in elucidating the molecular and cellular underpinnings of granuloma genesis, aggregations of immune cells that induce organ impairment in an array of diseases. The document harnesses single-cell sequencing and spatial transcriptomics to scrutinize granulomas procured from patients with sarcoidosis, a non-infectious granulomatous condition. The narrative unveils granulomas' adoption of transcriptional paradigms concurrent with lymphoid organ development and implicates a consortium of pathogenic macrophages, T cells, and fibroblasts in the process.
Sample Type
Human granulomas samples
Result—The Main Cell Types in Skin Granulomas are Macrophages, T Cells, and Fibroblasts
In a meticulous probe into the granulomas of enduring cutaneous sarcoidosis, scholars harnessed scRNA-seq on samples from lesional and non-lesional dermal layers, gleaning insights from about 56,000 single-cell transcriptomes of 12 diverse patients. The salient cellular constituents were macrophages, T cells, and fibroblasts, with an intricate automated analysis highlighting eight dominant cell categories. By juxtaposing non-lesional cellular transcriptional states with those of pristine control dermis, the investigators authenticated their methodological robustness. Spatial transcriptomics coupled with immunofluorescence staining reaffirmed the cellular dispersion and interactive dynamics within the granulomas.
Fig.2 The main cell types in skin granulomas are macrophages, T cells, and fibroblasts. (Krausgruber, 2023)
Result—The Cell Communication Between Immune Cells and Structural Cells Defines the Structure of Granulomas
By conducting a comprehensive analysis of ligand-receptor interactions across multiple cell varieties, it was revealed that GA macrophages, T cells, and fibroblasts secreted a myriad of chemokines and corresponding receptors, thereby positing potential intracellular communication. An array of genes related to inflammation have been found to be profoundly represented in the granulomas' spatial transcriptomics data. Critical markers like IFNG, LTB, and PECAM1, along with numerous integrins, highlight a complex interplay between T cells, macrophages, endothelial cells, and fibroblasts, with potential mediation of extracellular matrix components and collagen. The study also discerned a significant intensification of diverse immune regulatory mechanisms, marked by the expression of DPP4, CTLA4, PDCD1, and CD274, with additional evidence of a possible Th17.1 conducive cellular milieu owing to high expression of IL23 and IL23R within granulomas.
Fig.3 The granuloma structure is defined by the cellular crosstalk of immune and structural cells. (Krausgruber, 2023)
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Reference
- Krausgruber, T.; et al. Single-cell and spatial transcriptomics reveal aberrant lymphoid developmental programs driving granuloma formation. Immunity. 2023, 56(2):289-306.
